Cadmium Toxicity and the Antioxidant System [1 ed.] 9781616684631, 9781616681722

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Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved. Surai, P. F.. Cadmium Toxicity and the Antioxidant System, edited by A.C. Pappas, et al., Nova Science Publishers,

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved. Surai, P. F.. Cadmium Toxicity and the Antioxidant System, edited by A.C. Pappas, et al., Nova Science Publishers,

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CADMIUM TOXICITY AND THE ANTIOXIDANT SYSTEM

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Surai, P. F.. Cadmium Toxicity and the Antioxidant System, edited by A.C. Pappas, et al., Nova Science Publishers,

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved. Surai, P. F.. Cadmium Toxicity and the Antioxidant System, edited by A.C. Pappas, et al., Nova Science Publishers,

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CADMIUM TOXICITY AND THE ANTIOXIDANT SYSTEM A.C. PAPPAS,

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E. ZOIDIS, K. FEGEROS, G. ZERVAS Department of Nutritional Physiology and Feeding Faculty of Animal Science and Aquaculture Agricultural University of Athens, Greece

AND

P.F. SURAI Division of Environmental and Evolutionary Biology University of Glasgow, UK

Nova Science Publishers, Inc. New York

Surai, P. F.. Cadmium Toxicity and the Antioxidant System, edited by A.C. Pappas, et al., Nova Science Publishers,

Copyright © 2010 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works.

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Published by Nova Science Publishers, Inc. † New York

Surai, P. F.. Cadmium Toxicity and the Antioxidant System, edited by A.C. Pappas, et al., Nova Science Publishers,

CONTENTS

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Abstract Chapter 1 Chapter 2 Chapter 3 Chapter 4 Chapter 5 Chapter 6 References Index

Introduction Exposure Description of Adverse Effects Absorption and Metabolism Cadmium Interaction with Other Elements and the Antioxidant System Conclusion

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ABSTRACT Cadmium (Cd) is a toxic heavy metal of increasing environmental concern due to its wide variety of adverse effects. Living organisms are exposed to Cd via food, water and contaminated air. Studies in humans, animals and cultured cells revealed that Cd causes carcinogenesis in several organs and tissues; including lung, kidney, prostate, adrenals, testes and the hemopoietic system. Mutations in cultured cells, strand breaks in DNA and chromosomal aberrations reflect some of the frequently occurring adverse effects. Cadmium is absorbed from the gastrointestinal tract and the lung and is mainly accumulated in liver and kidney where it is bound to metallothionein (MT). Furthermore, recent studies reveal the presence of other proteins, besides MT, that bind or transport Cd. When Cd concentration exceeds the binding capacity of MT, the non-bound Cd causes toxicity possibly due to free radical induction and lipid peroxidation. These oxidative pathways may result in inhibition of DNA damage repair, depression of apoptosis, altered enzyme expression and activities, impairment of metabolism and energy balance. Cadmium metabolism is affected by the presence of other elements such as Zn, Fe, Se, Ca and Pb. These interactions affect the antioxidant defense system of the organism since Se, Fe and Zn are integral part of selenoproteins, catalase and superoxide dismutase respectively. Zinc has been demonstrated to protect from oxidative stress, cellular toxicity, apoptosis and necrosis induced by Cd. Cadmium often competes with Zn for important binding sites for gene regulation and enzyme activity. Zinc induces the synthesis of MT, which in turn eliminates many of the adverse effects of Cd. Iron deficiency causes an increase in Cd absorption in both mice and humans. However, addition of Fe in rats and pigs revealed a protective effect of dietary Fe on decreasing Cd uptake from the gastrointestinal tract and lowering its accumulation in various tissues.

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A.C. Pappas, E. Zoidis, K. Fegeros, et al. Selenium (Se) exerts protective effects on Cd toxicity by forming biologically inactive, insoluble Cd–Se complexes. Selenium may improve the protective effect of Zn in the prevention from Cd damage. Furthermore, selenoproteins can sequester Cd ions and scavenge free radicals. In comparison to Zn, Ca and Mg are relatively ineffective in reducing the carcinogenic effects of Cd. It is possible that Cd antagonizes the intestinal absorption of the Pb since joint exposure to Pb and Cd reduced concentrations of Pb compared to the Pb alone. Revealing Cd relation to the antioxidant system and other elements will enhance our understanding on the role of Cd in the environment.

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Keywords: Antioxidants, Cadmium; Carcinogenesis; Metabolism; Selenium; Zinc.

Surai, P. F.. Cadmium Toxicity and the Antioxidant System, edited by A.C. Pappas, et al., Nova Science Publishers,

Chapter 1

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INTRODUCTION Heavy metal pollution is one of the most important environmental problems. Industrial production and discharge of wastes containing different heavy metals can lead to environmental pollution. Examples of industrial production that may lead to heavy metal environmental pollution include but not limited to mining and smelting of metalliferous, surface finishing industry, energy and fuel production, fertilizer and pesticide industry, metallurgy, electroplating, electrolysis, electro-osmosis, leatherworking, photography, electric appliance manufacturing, metal surface treating, aerospace and atomic energy installation [1]. Three categories of heavy metals are of concern, including toxic metals (such as Hg, Cr, Pb, Zn, Cu, Ni, Cd, As, Co, Sn.), precious metals (such as Pd, Pt, Ag, Au, Ru) and radionuclide (such as U, Th, Ra, Am) [1]. Cadmium is the heavy metal that will be examined in this book not only because it is a pollutant but also because it is a known carcinogen for humans. Other recognized human carcinogens, include As, Be, Co, Ni and hexavalent Cr [2]. It is well established that Cd and Cd compounds such as Cd acetate, Cd carbonate, Cd chloride, Cd hydroxide, Cd nitrate, Cd oxide, Cd stearate, Cd sulfate, Cd sulfide and Cd-Cu alloy are human carcinogens based on findings on increased cancers on exposed workers and on findings in studies with experimental animals [3]. Cadmium is a group IIB metal that has an atomic weight of 112.41 g/mol. It is found naturally in the earth’s crust and is usually present in the environment as an inorganic salt (such as Cd oxide (CdO), Cd chloride (CdCl2), or Cd sulfate (CdSO4)) (Table 1) [4]. Moreover, Cd occurs naturally in the environment from the gradual process of erosion and abrasion of rocks and soils, and from singular events such as forest fires and volcanic eruptions.

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It is therefore naturally present everywhere in air, water, soils and foodstuffs. Although Cd may change chemical forms, the metal ion itself is not removed from the environment [5]. Accordingly, as the environment continues to be contaminated with this metal, there is an increasing risk of humans and other mammals being exposed to Cd. There are estimates that about 25,000 to 30,000 tons of Cd are released into the environment each year, with the major contributions coming from human activities, such as mining, burning of fossil fuels, incineration of municipal or industrial wastes, or land application of sewage sludge or fertilizer [6].

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Table 1. Cadmium physical properties and natural occurring levels Natural cadmium levels in the environment Atmosphere Earth's crust Marine sediment Sea-water Cadmium physical properties Chemical symbol Form Characteristics Melting point Atomic number Atomic weight Density

0.1 to 5 ng/m³ 0.1 to 0.5 µg/g ~1 µg/g ~0.1 µg/l Cd white, soft metal malleable, ductile and flexible 321°C 48 112.41 8.64 g/cm³

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Chapter 2

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EXPOSURE Cadmium was first discovered in Germany in 1817 as a by-product of the Zn refining process. Industrial applications for Cd were developed in the late 19th and early 20th Century. Cadmium-sulfide based pigments were used as early as 1850 and appeared prominently in the paintings of Vincent Van Gogh in the late 1800s. Thomas A. Edison in the United States and Waldemar Junger in Sweden developed the first Ni-Cd batteries early in the 20th Century. However, the most significant early use of Cd was as a corrosionprotection coating on steel. Cadmium has a large array of uses, and its production has climbed steadily during the last forty years, although certain applications have recently declined. Industrial exposure levels in some industries were very high through the 1950's and 60's [7]. In the last two decades, however, occupational exposures have dropped, following the dramatic reduction of exposure limits in most industrialized nations [6, 8]. In USA, the demand for Cd in the nickel-cadmium (Ni-Cd) battery industry is strong despite the drop in other areas, like coatings and pigments [6]. Many scientists and policy makers acknowledge the need to continue reducing exposures to this very toxic metal. Exposure to Cd may occur by occupational and environmental sources.

A. OCCUPATIONAL EXPOSURES Inhalation of dust and fumes and incidental ingestion of dust from contaminated hands, cigarettes and food is the major route of occupational exposure [3]. Regarding the occupational exposures, a list of possible sources

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is provided. Industries are listed in order of potential exposures, from higher to lower.

1. Nickel-Cadmium Battery Manufacturing During manufacture of both industrial and household Ni-Cd batteries significant exposure of workers to Cd dusts may appear. Critical, for exposure stages during manufacture include plate making, impregnation, plate preparation and assembly. In some cases, health effects from Cd exposure may be confounded by associated exposures to Ni in this environment [6, 9].

2. Zinc Refining/Cadmium Smelting and Production

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Deposits of Cd occur naturally in Zn ores. Cd is produced as a byproduct during Zn refining. About 80% of Cd production is associated with Zn production, while the other 20% is associated with Pb and Cu byproduct production [6].

3. Cadmium-Containing Pigment Production Cadmium pigments such as Cd sulfide and Cd selenosulfide are produced as powders, pellets, pastes and liquids. Such kinds of pigments are mainly used for the coloring of plastics. About 25% of worldwide production of Cd is used in pigments. High inhalation exposures may occur in calcining, crushing and milling operations [9], especially when the Cd product is present in powder form. Although wet system operations provide lower inhalation exposures they can be associated with increased ingestion exposure, resulting in high Cd-blood levels [10].

4. Dry Color Formulating Cadmium pigments may be formulated into custom color concentrates prior to use in plastics and ceramics. Producers of color concentrates are generally very small companies. Intermittent and highly variable exposures to

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Cd occur in material handling, mixing of dry pigments with other materials, grinding, or cleaning [9, 10].

5. Cadmium-Based Stabilizer Production Cadmium stabilizers are used primarily in the production of PVC and other plastics. During PVC production, exposures to dry and wet products can occur. Such kinds of exposures are described by the Occupational Safety and Health Administration (OSHA) as intermittent. High exposures can occur in Cd oxide charging, drying, crushing and blending operations [9, 10].

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6. Metal Plating with Cadmium-Containing Materials One of Cd properties is that it is highly corrosion resistant. This is why it is widely used to plate metal parts used in general industrial hardware as well as in the automotive, electronics, marine and aerospace industries. As much as 35% of worldwide Cd production is used in plating. Cadmium plating is done by means of electroplating or mechanical plating operations. OSHA reports that at mechanical plating operations, less than 10% of the workforce is exposed to Cd, though exposures tend to be higher than those in electroplating [11].

7. Production of Cd Alloys Cadmium is used in production of copper alloys to increase the mechanical strength and wear resistance of copper wire conductors. It is also used in the production of alloys with Zn, Pb, Ag or Sn. Workers of such companies may be exposed to Cd fume during melting and casting operations [12].

8. Lead Smelting and Refining Lead concentrates that are processed in Pb smelting and refining operations contain Cd contaminants. Cadmium exposures occur in material handling, sinter plants, furnace areas, refining and casting. During these

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operations, workers may experience combined exposures to Pb, Cd and other materials [11].

9. Iron and Steel Production Cadmium is present as a trace contaminant in raw materials used for steelmaking. Exposures to Cd may occur during furnace operations, welding and maintenance work [11].

10. Coal-Fired Electrical Utilities and Garbage Incineration The fly ash, cinders and flue gases produced in coal burning and garbage incineration utilities may contain high levels of Cd. In these utilities, exposures may occur during equipment malfunctions, or during inspection and maintenance of boilers, ovens and filters [9, 10].

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Other Occupations Other occupations of the general industry that may be exposed to Cd include but not limited to [6, 11, 13-16]:

1. Chemical Mixers If chemical or mechanical mixing involves Cd compounds such as stabilizers, pigments, metallic coatings or substances used for fungicides, then exposure may occur.

2. Electroplaters Electroplaters that work in industries providing decorative or protective surfaces, may be exposed to Cd if they plate with Cd-containing materials.

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3. Furnace Operators and Molders These workers may be exposed to Cd fumes released from molten metal during smelting, refining, casting, forging and molding operations.

4. Kettle Operators Workers, who operate, load or tend kilns, kettles, ovens or furnaces may be exposed to Cd. Such exposures may occur while treating Cd containing materials like glazes, paints or other coatings.

5. Workers in Flame Hardening

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Workers of flame-hardening machines, electronic induction machines, furnaces and baths which are used to harden, anneal or heat-treat metal parts may be exposed to Cd, if the materials used are coated with or contain Cd.

6. Equipment Cleaners Workers that clean electrostatic precipitators, process equipment and process areas may be exposed if these equipment or areas are contaminated with Cd containing dust.

7. Metal Machine Operators Machinists, grinders, filers, machine tool operators and others may be exposed when grinding or forming metals coated with Cd.

8. Painters Cadmium is used in some metal sprays and paints. Hot dip lines, metal spraying machines and hand held power tools are used to coat metal, plastic and other materials with Cd-containing paints. Workers may be exposed to Cd while operating such equipment.

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9. Mechanics and Industrial Installation Workers Workers that maintain, repair, install or dismantle machinery and heavy equipment like automotive, motorcycle, aircraft, farm and heavy equipment may be exposed to Cd. Such kinds of workers include but not limited to mechanics, plumbers, pipefitters, steamfitters and boilermakers.

10. Other Metal Workers When welding, brazing or soldering is done with Cd containing base metals, rods or solders, exposure of workers to Cd may occur. In addition to welders, brazers and solderers, other kind of workers that may be exposed include structural steel workers, metal pattern makers, metal fabricators and assemblers.

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11. Ceramists Ceramists and ceramics teachers may be exposed to Cd if they use coloring compounds that contain Cd.

12. Artists, Theatre and Television Crafts Workers in artwork and theatre crafts may be exposed to Cd if they use dry pigments, paints, pastels, pottery and enameling colorants, low melting silver solders, and metal alloys that contain Cd.

13. Jewellery Producers Jewellery workers may be exposed to Cd if they handle solders that contain Cd.

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B. ENVIROMENTAL EXPOSURES Environmental sources include air, water, soil, plants, food and consumer products. Industrial processes such as metal production activities, fossil fuel combustion and waste incineration can produce very fine Cd-containing particles that contaminate ambient air. The most abundant species of Cd in the air is Cd oxide, chloride and sulfate. Cadmium can travel long distances in the atmosphere and then deposit onto surface soils and water, which can result in elevated Cd levels even in remote locations [6]. Processes that can contaminate water with Cd include natural weathering processes, discharge from industrial facilities or sewage treatment plants, atmospheric deposition, leaching from landfills or soil, or phosphate fertilizers. Other sources include leaching from pipes in the distribution system because Cd is present in galvanized Zn coatings and in solders used to join Cu pipes. Cadmium concentration in water is inversely related to the pH and the concentration of organic material in the water. Because Cd exists only in the +2 oxidation state in water, aqueous Cd is not strongly influenced by the oxidizing or reducing potential of the water [6, 17, 18]. Cadmium in the soil may originate through atmospheric emissions, direct application and contamination. Examples of direct application sources include phosphate fertilizers, phosphogypsum, sewage sludge, composted municipal solid waste, and residual ashes from wood, coal, or other types of combustion. Contamination sources include industrial site contamination, mine waste dumps and corrosion of metal structures [6]. Markedly elevated levels may occur in topsoils near sources of contamination. Uptake of soil Cd by plants would account for Cd found in food. Cadmium levels in food can vary greatly depending on the type of food, agricultural and cultivating practices and contamination. In general, leafy vegetables, such as lettuce and spinach, and staples, such as potatoes and grains, contain relatively high values of Cd [19]. Most notably, food items that contain high levels of Cd are dry roasted peanuts (0.051 mg/kg), smooth peanut butter (0.056 mg/kg), shredded wheat cereal (0.057 mg/kg), boiled spinach (0.125 mg/kg), potato chips (0.062 mg/kg), apricots (0.17 mg/kg), creamed spinach for infant and junior foods (0.090 mg/kg) [20, 21]. Bioavailability of Cd from cereals grains and foods is about 5-10% and affected by factors such as binding of Cd to proteins or phytates. Cadmium binds to inositol phosphates (InsP) containing different numbers of phosphate groups. In detail, Cd binds to InsP6, InsP5, InsP4 and InsP3 less strongly than Cu and Zn do at low pH values, in the vicinity of 4 [22]. Peanuts, soybeans

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and sunflower seeds have naturally high levels of Cd. Meat and fish contain lower amounts of Cd, with the exception of animal organ meats, such as kidney and liver, as these organs concentrate Cd [23]. Seafood, shellfish eaters have high background levels that may increase the risk for experiencing Cdinduced adverse effects by the end of their lives [24]. The National Research Council of the United States indicates that the maximum tolerable level of Cd for domestic animals is 0.5 ppm [25]. The Cd content of forage crops should not exceed 0.5 ppm in order to limit the concentration of Cd in the liver and kidney of animals feeding on these crops to protect humans against Cd toxicity through consumption of these organs [26]. Environmental contamination has led to severe Cd-related disease in Japanese populations who consumed rice grown in Cd-contaminated irrigation water [27-32]. Consumer products that include Cd include batteries, pigments, coatings and platings, stabilizers for plastics and nonferrous alloys and photovoltaic devices [6]. Cadmium is found in small amounts in tobacco. Although the Cd content of cigarettes is much lower than that of food, Cd is absorbed much more effectively by the lung than the gut. For smokers, who are not occupationally exposed to Cd, smoking is usually the main source of exposure. Cadmium intake from smoking can substantially increase total Cd exposure for occupationally exposed workers [33]. Absorption of Cd in tobacco smoke is mainly through the lung, although occupationally exposed smokers may also ingest some Cd from contamination of hands and cigarettes [14]. Smoking one pack of cigarettes per day might result in the exposure to approximately 10 μg and absorption of 1 to 3 μg Cd (10-30% of the Cd in inhaled smoke generally passes through the pulmonary epithelium into systemic circulation), an amount approximately equal to the amount absorbed from the diet. An average German citizen has a daily intake of 30–35 μg Cd; 95% of this taken up with food and drinks. An average smoker has an additional intake of 30 μg per day [34]. The International Agency for Research on Cancer (IARC) has classified Cd as a Category I carcinogen [35]. Research findings indicate that the carcinogenic effects of Cd are related to the activation of proto-oncogene [36, 37]. Cadmium has been ranked as high as seventh on the Top 20 Hazardous Substances Priority List by the Agency for Toxic Substances and Disease Registry and the U.S. Environmental Protection Agency [38]. The warning of health risks from Cd pollution were issued initially in the 1970s [39]. The guideline for a maximum recommended Cd intake set by the World Health Organization is 1 μg Cd per kg body weight per day (kg/d) [40]. Thus, the provisional tolerable weekly intake is 7 μg/kg [41]. However, Satarug et al.,

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[42] stated that exposure levels of 30-50 μg Cd/d for an adult (about 0.6 μg/kg/d) could increase the risk of bone fracture, cancer, kidney dysfunction, and hypertension. Thus, the recommended guideline for maximum Cd intake of 1 μg/kg/d appears to be too high to ensure against renal dysfunction resulting from dietary Cd intake. The European Food Safety Authority recommends that the daily dietary intake of Cd should not exceed 0.36 μg/kg/d, corresponding to a weekly dietary intake of 2.52 μg Cd/kg body weight [43].

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Chapter 3

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DESCRIPTION OF ADVERSE EFFECTS Cadmium has an extremely long biological half-life ranging from 10 to 30 years something that makes it a cumulative toxin [43, 44]. Cadmium has been classified by the International Agency for Research on Cancer as a human carcinogen [3, 19, 34, 45]. Concerns about the effects of Cd on human health have led to numerous guidelines and regulations limiting its concentrations in soils and food and allowable human intakes. The effects of Cd exposure include, but not limited to, acute ones, chronic respiratory ones, effects on kidneys, skeletal system and cancer. Acute effects in workers occur mainly because of exposures to Cd fume in welding or soldering, especially when this takes place in poorly ventilated working places. Overexposure to Cd fume (usually from welding or cutting materials containing Cd) can cause tracheo-bronchitis (inflammation in the trachea and bronchial tubes), pneumonitis (inflammation of the lungs) and pulmonary edema (accumulation of fluid in the lungs) [7, 46-49]. The American Conference of Governmental Industrial Hygienists has estimated that 20% of those who experience acute pulmonary responses to Cd fume die as a result [50]. Even a couple of hours of exposure to a few milligrams per cubic meter can have fatal results. Inflammation may not become evident until a few hours after exposure [8]. Initial symptoms include irritation and dryness of the nose and throat, cough, headache, dizziness, weakness, chills, fever, and chest pain. Respiratory effects may also occur because of high exposures to Cd dust, but are usually less severe than those due to Cd fume. Survivors of Cdrelated pneumonitis may go on to develop emphysema several years later [7, 46]. Ingestion of Cd can be associated with salivation, choking attacks,

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persistent vomiting, abdominal pains, spasms of the anal sphincter, vertigo and loss of consciousness [7, 14]. Pulmonary effects due to Cd exposure may vary depending on whether exposure is to a fume or dust, the size of particles, and solubility of the compound involved. Examples of chronic respiratory disorders include: emphysema, chronic bronchitis, pulmonary fibrosis and olfactory impairment. The first impairment of the pulmonary system associated with Cd was emphysema. Furthermore, morbidity studies in Cd exposed workers identified shortness of breath, obstructive patterns of lung function and bronchitis. Forced vital capacity of workers exposed to Cd levels greater than 0.2 mg/m3 for six years or more, was found to be decreased compared to physiological one [51]. Increases in deaths caused by chronic obstructive lung disease have been observed in several independent studies of workers exposed for long periods to high levels of Cd in air. In these studies, the average Cd exposure period of workers was a decade or more. In some cases, fatal cases of emphysema have been reported for workers with less than two years exposure. These workers were exposed to Cd levels of 0.1 to 0.4 mg/m3 in air [52-54]. Workers exposed to high levels of Cd for long time were diagnosed with pulmonary fibrosis [53]. This effect has been replicated in animal studies where it appears to result from an inflammatory reaction in the lung due to inhalation of soluble Cd compounds such as Cd oxide and Cd sulphide [11]. Olfactory impairment (loss of a sense of smell) associated with Cd exposure has been reported by a number of investigators. Workers with olfactory impairment due to Cd exposure are likely to have additional health problems such as renal effects [55-58]. About half the Cd absorbed by the body is stored in the kidneys where it produces structural and functional changes [7].The kidney is considered the critical organ in long-term, low-level exposure to Cd. Kidney effects from exposure to Cd have been recognized since the late 1940's. Cadmium is especially toxic to the proximal tubular cells where it accumulates over time and may cause renal dysfunction. After high and/or prolonged exposure, the tubular damage may progress to glomerular dysfunction, tubular proteinuria, kidney stones and eventually to renal failure. In detail, long-term exposure to Cd may damage the glomerular membrane of the kidney, leading to the excretion of high molecular weight proteins such as albumin, γ-globulins (IgG and IgA), and α2-macroglobulin. Increased urinary concentrations of albumin in Cd-exposed workers are not a sign of glomerular damage, but result mainly from tubular dysfunction [59-62]. Glomerular dysfunction is indicated by high serum creatinine concentration and low glomerular filtration rate [63-65].

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Proteinuria is the first sign of Cd-related damage to the kidneys. Indicative proteins include β2-microglobulin and retinol-binding protein. These proteins are normal constituents of plasma, and are normally filtered through the glomerular membrane and then reabsorbed from the proximal tubules of the kidney. Proteinuria is a sign of damage to the tubules. This damage is permanent, and may progress even after retirement or removal from exposure [66]. Renal tubular dysfunction may progress and result in aminoaciduria, glycosuria, wasting of Ca and phosphate, formation of kidney stones and altered Ca metabolism leading to bone disease [63-65]. Cadmium can also cause bone demineralization, either through direct bone damage or indirectly because of renal dysfunction. Effects on bone first came to light in the human population when it was determined that long-term oral exposure to dietary Cd, in conjunction with low Ca and vitamin D intake, were important factors in the production of the severe bone degeneration (itai-itai disease) observed in Japanese women consuming Cd-contaminated rice [67]. Other adverse effects of Cd in the skeletal system include loss of bone density and mineralization, osteomalacia and osteoporosis [19, 28-30, 34, 68]. Cadmium’s long residence time could enhance the probability of neoplasmatic transformation [4, 69]. Laboratory and animal studies have provided strong evidence for carcinogenic effects of Cd. There are definite species and strain-related differences in sensitivity to Cd carcinogenicity. The potential mechanism(s) of Cd carcinogenesis may include mutations in cultured cells [70], strand breaks in DNA and chromosomal aberrations [71], enhanced proliferation, depressed apoptosis, and/or altered DNA repair [72, 73] as well as induction of oxidative DNA damage and epigenetic alterations (such as gene silencing by changes in DNA methylation patterns) [74, 75]. The strongest link has been with lung cancers but interpretations vary between recognition [76] and equivocal or no support [73]. In detail, increase in the occurrence of lung cancer has been reported in several studies of Cdexposed workers. However, there is some controversy about how much of the excess mortality from lung cancer in Cd-exposed workers is due to Cd and how much due to confounding exposures to As or to Ni [8, 11, 14, 15, 54, 77]. In addition, the lung cancer effects of Cd were confirmed in rats at exposure levels below the current occupational limits [8]. Other target tissues of Cd carcinogenesis in animals include injection sites, adrenals, testes, and the hemopoietic system. Exposure to Cd causes damage in the testes and results in infertility in experimental animals. In detail, necrosis of the testes due to vascular collapse is a result of a high dose of Cd [45]. In experimental animals, Cd causes testicular cancer and sarcomata [78].

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Cadmium can also cause prostatic proliferative lesions, including adenocarcinomas, after systemic or direct exposure [44]. In studies with industrial workers a link between Cd exposure and human cancer e.g. of the bladder, kidney, lung and prostate was noted [16, 79]. Regarding carcinogenity, it seems that Cd induces two types of genes: genes coding for detoxification and other cytoprotective proteins like MT, enzymes of glutathione synthesis, heat shock (stress) proteins, and Zn transporter proteins and early genes and proto-oncogenes related to cell proliferation control. The concentrations of Cd required for the induction of MT and proto-oncogene are low. Lack of expression of MT protein, under basal and Cd-stimulated conditions, has been regarded as one of the major underlying causes of tissue susceptibility to Cd toxicity and/or carcinogenicity. This metal is the strongest inducer of MT promoters. At low concentrations, Cd and As are relatively specific inducers of early genes, whereas by elevated Cd concentrations, the stress response seems to be the consequence of more severe cytotoxic damage. The induction of early genes by Cd is mediated by interference of its ions with cellular signal transduction mechanisms [2]. Cadmium induced apoptosis is attributed to modulation of protein kinase and phosphatase activities and transcription factors [2, 80]. Mitogen-activated protein kinases, mitochondria, caspases and reactive oxygen species (ROS) pathways all seem to play a role in cytotoxicity [81-90]. Chromosomal damages induced by Cd in peripheral lymphocytes include clastogenic and aneugenic effects [91]. Cadmium can produce genotoxic and mutagenic events but generally high doses are required. In rodents, low, non-toxic doses of Cd did not induce DNA damage but had a deleterious effect on DNA repair [45]. Similarly, in cultured cells Cd produces DNA damage only at very high levels [45]. The suppression of DNA repair by Cd would potentially add to the population of cells with damaged DNA. Apoptotic cell death is an ongoing, normal event in the control of cell populations and will cause elimination of cells with damaged genetic material. In this context, chemically induced apoptosis can be very effectively blocked by Cd. This may be a critical step in the pathogenesis of Cd-induced malignancies [44, 92]. Another way Cd may exert its toxic effect is by mimicking the in vivo effects of estrogen in the uterus and mammary gland. In fact, Cd may be a mimic of the effects of estradiol in ovariectomized female rats by activating the estrogen receptor. In contrast, Zn binds to the cysteines in the DNA binding domain but does not activate the estrogen receptor [93]. Hair samples have been used for noninvasive diagnosis of Cd toxicity in humans. It was found that Pb and Cd accumulation in hair were associated

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with higher blood Pb concentration and hair Pb influenced the hair Cd accumulation. However, a strong positive correlation in Pb concentrations and a non-significant correlation in Cd concentrations between blood and hair suggest that Pb but not Cd in hair can be used reliably to indicate contamination of blood in cattle [94]. Certain treatments modify Cd carcinogenicity, including administration of Zn, which prevents Cd-induced injection site and testicular tumors while facilitates prostatic tumor formation. Diets deficient in Zn increase the progression of testicular tumors but reduce the progression of prostatic tumors. Furthermore, clay could be used against Cd toxicity. Clay minerals can protect against toxicity of various natural or synthetic chemical products, including mycotoxins and heavy metal ions [95]. The mechanism of protection by clay minerals has been primarily attributed to the adsorption and cation exchange capacity to reduce the bioavailability of the toxins or the heavy metal ions in the gastrointestinal tract when added to contaminated diet [96]. Egyptian montmorillonite (EM) effectively removed Cd2+ ions from aqueous solution in dose dependent fashion. This study indicated that exposure to Cd2+ ions resulted in severe toxicological effects on biochemical, histological and histochemical parameters typical to those reported in the literature. The in vivo study showed that EM induced protective effects against these toxicological effects of Cd2+ ions. Thus, EM seems to be an effective candidate for the removal of Cd2+ ions from aqueous solution and for the protection against Cd2+ ions toxicity with no side effects [95].

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Chapter 4

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ABSORPTION AND METABOLISM Humans are generally exposed to Cd by three routes, inhalation and ingestion and through the skin. However, absorption of Cd percutaneously is relatively insignificant. Pulmonary absorption of Cd is relatively more efficient than the absorption of Cd along the gastrointestinal tract. It has been shown that the efficiency of gastrointestinal absorption of Cd is only about 12% in mice and rats, 0.5-3% in monkeys, 2% in goats, and 5% in pigs and lambs and 16% in cattle [19]. In humans, the efficiency of gastrointestinal absorption of Cd has been reported to be approximately 3-8% of the ingested load [6]. In rodents, most of the absorption of Cd appears to occur primarily in the duodenum and early jejunum [97]. The chemical form of Cd affects its intestinal uptake and subsequent distribution to target tissues. In rodents, intestinal accumulation and retention of Cd was greater after oral exposure to CdCl2 than to Cd complex with proteins [98]. Cadmium interacts with, and competes for, binding site(s) on membrane proteins involved in the transport of essential elements (Ca, Fe and Zn) into target epithelial cells [99]. Cadmium ions enter into certain transporting epithelia via endocytosis of proteins that contain Cd [19]. When Cd ions bind to MT, albumin, or other proteins, the conjugates that are formed can serve as substrates for absorptive and/or receptor-mediated endocytotic transport. Cadmium and low-molecular-weight thiols can form S-conjugates, that act as molecular homologs or mimics at the sites of specific transport proteins [100103]. Metallothionein is a low molecular weight, cysteine-rich, intracellular protein with high affinity for both essential and non-essential metals. MT’s high affinity for metals provides not only a mechanism for protection against the toxicity of Cd but also the maintenance of homeostasis of some essential

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metals in mammals [104, 105]. There are four isoforms of MT, namely MT-I, MT-II, MT-III and MT-IV [106, 107]. Isoform-I and -II are expressed in all tissues. MT-III is expressed mainly in the brain [108] and MT-IV in squamous epithelia [109]. Protection against metal toxicity has been attributed primarily to MT-I and -II, although MT-III is thought to play a role in Zn homeostasis in neurons [110] while the function of MT-IV remains unknown. Retention and transport of Cd from within enterocytes is mainly attributed to MT which plays an important role in the distribution of Cd within the mucosa of the small intestine after the ingestion of Cd. Intestinal retention of Cd seems to reduce the amount of Cd entering into circulation thus, decreasing the amount of Cd delivered to target organs, such as the liver and kidneys [111]. Several potential mechanisms have been proposed to explain intestinal handling of Cd. These include but not limited to endo/exocytotic mechanisms, direct release after intoxication/injury of enterocytes and disruption of cell junctional complexes [19, 112, 113]. The intestinal epithelium is crossed by Cd-MT, either by passing through the relatively leaky junctional complexes between adjacent enterocytes, and/or by a mechanism in which Cd-MT is taken up by endocytosis [19]. Prozialeck [113] suggested that Cd can disrupt junctional complexes between epithelial cells by altering the Ca-dependent Ecadherin/β-catenin system, which is part of the zonula adherens of the junctional complex. Endocytosed proteins are generally not exocytosed out of transporting epithelial cells but rather are degraded intracellularly in lysosomes by hydrolytic enzymes. Exocytosis of Cd-MT seems improbable since MT does not contain a leader sequence that would promote its exocytosis from cells. Additionally, Cd-MT, which is transported into and/or is formed within enterocytes, is released when the cells become senescent or intoxicated. Release of Cd-MT under these circumstances could provide a direct pathway for Cd-MT to enter into the capillaries of mucous membranes [19]. Intestinal Cd transport is mediated by several transporters such as the divalent metal transporter 1 (DMT1), the human Zn-regulated transporter (hZTL1), the Zn transporter ZNT1 and the metal transport protein 1 (MTP1) [114-120]. DMT1 is a proton-coupled, membrane potential-sensitive, transport protein that is capable of transporting a number of divalent cations including Cd2+, Fe2+, Zn2+, Cu2+, Mn2+, Co2+, Ni2+, and Pb2+. It is known that Fe2+ and Cd2+ are transported by DMT1 through a mechanism of ionic mimicry [115, 117, 119]. Expression of DMT1 has been found in numerous tissues such as gastrointestinal tract, liver, kidney, lung, heart, brain and testis [118]. Furthermore, in humans, Zn and Cd may compete for a luminal membrane transporter in enterocytes that is not DMT1 but rather the human, Zn-

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.

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regulated, transporter of Zn (hZTL1) [114,115]. The identification of the Zn transporter ZNT1 in the basolateral membrane of enterocytes [121] and transport studies with isolated pig apical membrane vesicles point to a common site of transport or binding of Zn and Cd [122, 123]. Finally, in rodents, a DMT1 homologous Fe transporter, namely metal transport protein 1 (MTP1) has been identified and may be involved in the transport of Cd [116]. When Cd enters into systemic circulation, from the lungs or intestines, it is delivered to target organs. Cadmium is carried in the blood by albumin, globulins, low molecular-weight thiols, such as Cys, homoCys, and glutathione (GSH), MT, and transferrin [19, 124, 125]. Cadmium is then taken up by the liver and kidneys where it remains for several years [4, 126, 127]. Joshi et al., [128] suggested that Cd-ferritin complexes may indeed serve as a route of entry of Cd into hepatocytes and that ferritin may serve as a detoxifying protein due its ability to bind a number of cationic forms of several elements. Additionally, Cd may enter into hepatocytes by passing through Ca channels [19, 129]. Cadmium is localized preferentially in the liver where it induces the synthesis of MT (mainly MT-I and -II). This induction of MT appears to provide hepatocytes with a source of protection from the cytotoxic effects of Cd [130, 131]. The large amounts of MT protein produced in hepatocytes after exposure to Cd are related to the large amounts of Cd taken up the cells. Reeves et al., [132] found using MT-null mice (that did not produce intestinal MT) that these accumulated Cd in the intestine to the same extent as mice with normal MT production. These data suggest the presence of another intestinal component besides MT that binds Cd [133]. Large fractions of Cd, which are not absorbed enterically pass through the lumen of both the small and large intestines and are excreted in the feces [32]. The major source of Cd that is excreted in the feces is derived from the hepatocellular secretion of Cd into the biliary system. In humans exposed to Cd via oral and/or pulmonary routes, the kidney is by far the primary organ affected adversely by Cd [4]. After oral administration of Cd-MT the ratio of the concentration of Cd in the kidney to the concentration of Cd in the liver was higher than the ratio after oral administration of CdCl2. This is because Cd-MT or cysteine (Cd-(Cys)2) is in a form that permits Cd ions to be delivered to and taken up more readily by the kidney epithelium [134] . Initially, the amount of Cd filtered by the nephrons is low (1–2% of the dose) however, there is indication that the urinary excretion of Cd increases after Cd-induced renal tubular damage [19, 135].

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Chapter 5

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CADMIUM INTERACTION WITH OTHER ELEMENTS AND THE ANTIOXIDANT SYSTEM Free radicals are implicated in the initiation or progression phase of various diseases, like cardiovascular disease, cancer, cataract, rheumatoid arthritis and a variety of degenerative diseases (Table 2). Under physiological conditions, a balance between the amount of free radicals generated in the body and the production of antioxidants exists. External sources such as radiation and pollution can increase free radical generation (Table 3). During evolution, living organisms have developed specific antioxidant protective mechanisms to deal with ROS and reactive nitrogen species (RNS) [136] (Table 4). Therefore, it is only the presence of natural antioxidants in living organisms that enables them to survive in an oxygen-rich environment [137]. While ROS are predominantly implicated in causing cell damage, they also play a major physiological role in several aspects such as intracellular signal transduction, regulation of gene expression, regulation of the cytosolic Ca concentration, regulation of protein phosphorylation, activation of certain transcription factors, such as nuclear factor-kappa B (NF-κB) and the activator protein 1 (AP-1) family factors, and intracellular killing of bacteria by neutrophils and macrophages [37, 138-145] (Table 5).

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Table 2. Free radical involvement in the development of human diseases Liver Reperfusion Toxic effects of chemicals: halogenated hydrocarbons, quinones, iron, acetaminophen, ethanol Endotoxin Kidney Autoimmune nephrosis:inflammation Toxic effects of chemicals: aminoglycosides, heavy metals Lung Normobaric hyperoxic injury Bronchopulmonary displasia Toxic effects of chemicals: paraquat, bleomicin Emphysema Asbestosis Idiopathic pulmonary fibrosis Heart and cardiovascular system Atherosclerosis Hemochromatosis Reperfusion: after infraction or transplant Selenium deficiency (Keishan disease) Toxic effects of chemicals: ethanol, doxorubicin Myocardial infarction Gastrointestinal tract Reperfusion Toxic effects of chemicals: nonsteroidal and anti-inflammatory agents, alloxan, iron Pancreatitis, Colitis, Intestinal ischemia, Gastric ulcers

Eye Retionopathy of prematurity Photic retinopathy Macular degeneration Ocular hemorrhage Cataracts Muscle Muscular dystrophy Over-exercising Skin Radiation (UV or ionising) Thermal injury Toxic effects of chemicals: tetracyclines stimulating photosensitization Contact dermatitis Porphyria Brain and nervous system Parkinson's disease Alzheimer's disease Tardive dyskinesia Neuronal ceroid lipofuscinosis Neurotoxins Hypertensive cerebrovascular injury Allergic encephalomyelitis Multiple sclerosis Inflammatory-immune system Glomerulonephritis Vasculitis Autoimmune disease Lupus erythermatosus Reumatroid arthritis

Surai, P. F.. Cadmium Toxicity and the Antioxidant System, edited by A.C. Pappas, et al., Nova Science Publishers,

Cadmium Toxicity and the Antioxidant System Blood Malaria Various anemias Protoporphyrin photooxidation Toxic effects of chemicals: phenylhydrazine, primaquine and related drugs, sulfonamides, lead Favism Fanconi's anemia

Miscellaneous/general Aging AIDS, Cancer, Diabetes Inflammation Trauma Ischemia/reperfusion Radiation injury Rheumatoid arthritis and lupus Toxic effects of chemicals: alloxan (diabetes), iron overload Acute pancreatitis, Amyloidosis

Adapted from [149].

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Table 3. Internal and external sources of free radicals Internally generated

External sources

Mitochondria Phagocytes Xanthine oxidase Reactions with Fe2+ or Cu+ Arachidonate pathways Peroxisomes Inflammation Biomolecule oxidation

Cigarette smoke Radiation UV light Pollution Certain drugs Chemical reagents Industrial solvents

Adapted from [149].

Table 4. Reactive oxygen and nitrogen species Radicals Alkoxyl, RO* Hydroperoxyl, HOO* Hydroxyl, *OH Peroxyl, ROO* Superoxide, O2* Nitric oxide, NO* Nitrogen dioxide, NO2*

25

Non-radicals Hydrogen peroxide, H2O2 Hypochlorous acid, HOCl Ozone, O3 Singlet oxygen, 1O2 Peroxynitrite, ONOONitroxyl anion, NONitrous acid, HNO2

Adapted from [149].

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Table 5. Some regulatory functions of free radicals Type of radical Nitric oxide (NO*)

Source of radical Nitric oxide synthase

Superoxide (O2-*) and related ROS

NAD(P)H oxidase

Superoxide and related ROS

Any source

ROS

Any source

Physiological process Smooth muscle relaxation (control of vascular tone) and various other cGMPdependent functions; Specific role in signal transduction events leading to sperm capacitation Control of ventilation; Control of erythropoietin production and other hypoxia-inductible functions; Smooth muscle relaxation; Signal transduction from various membrane receptors/enhancement of immunological functions Oxidative stress responses and maintenance of redox homeostasis; An increased intracellular ROS level stimulates cell proliferation, apoptosis and differentiation depending on the relative concentration of oxidants in the cell; Promotes physiological capacitation in sperm allowing the acquisition of fertilizing capacity Activation of a variety of kinases including Src kinase family, protein kinase C, mitogen-activated protein kinase (MAPK), receptor tyrosine kinases and transcription factors such as AP-1 and NF-B; Modification of redoxsensitive proteins (e.g. thioredoxin) affecting stress kinases

Adapted from [149].

The antioxidant system is mainly comprised of natural fat-soluble antioxidants (vitamins A, E, carotenoids, ubiquinones); water-soluble antioxidants (ascorbic acid, uric acid, taurine); antioxidant enzymes (glutathione peroxidase (GSH-Px), catalase (CAT) and superoxide dismutase

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(SOD)); thiol redox system (GSH/GSH reductase/glutaredoxin/GSH-Px) and the thioredoxin (Trx) system (thioredoxin/thioredoxin peroxidase/thioredoxin reductase (TrxR)) [146]. The antioxidant system is located in organelles, subcellular compartments or the extracellular space for maximum protection. Thus, the antioxidant system of the cell includes three major levels of defense (Figure 1). The first level is responsible for prevention of free radical formation. It removes precursors of free radicals or inactivates catalysts and consists of three antioxidant enzymes namely SOD, GSH-Px, CAT and metalbinding proteins (such as transferrin, lactoferrin, haptoglobin, hemopexin, metallothionein, ceruloplasmin, ferritin, albumin and myoglobin) thus; metal sequestration is an important part of extracellular antioxidant defense [147149]. This first level of antioxidant defense is not sufficient to completely prevent free radical formation in the cell. Some radicals escape and initiate lipid peroxidation and cause DNA and protein damages (Table 6). Therefore, the second level of defense consists of chain-breaking antioxidants (vitamin E, ubiquinol, carotenoids, vitamin A, ascorbic acid, uric acid) and some other antioxidants. Glutathione and thioredoxin systems also have a substantial role in the second level of antioxidant defense. Vitamin E performs only half the job in preventing lipid peroxidation by scavenging free radicals and forming hydroperoxides [149]. Selenium containing enzymes that are involved in antioxidant mechanisms include at least 25 selenoproteins [146]. Vitamin E and Se work in a tandem and even very high doses of dietary vitamin E cannot replace Se, which is needed to complete the second part of antioxidant defense. Thus, Se as an integral part of the GSH-Px, thioredoxin reductase and other selenoproteins belongs to the first and second levels of antioxidant defense [136]. Table 6. Effect of free radicals on DNA damages Radical

Effect

ROO* OH* O2*-, H2O2 ONOO-

Guanine oxidized All four bases are affected No base changes Xanthine, hypoxanthine, 8nitroguanine are affected

Adapted from [149].

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Figure 1. Levels of antioxidant defence

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Adapted from [149].

Glutathione is the most abundant non-protein thiol in avian and mammalian cells, providing them with their reducing milieu [150]. Cellular GSH plays a key role in many biological processes including: synthesis of DNA and proteins, cell growth and proliferation, regulation of apoptosis, immune regulation, transport of amino acids; xenobiotic metabolism and redox-sensitive signal transduction [151]. Furthermore, GSH thiolic group can react directly with several ROS including superoxide anion, hydroxyl radicals, alkoxyl radicals and hydroperoxides [148, 152, 153]. Most crucial role of GSH is as free radical scavenger, particularly effective against the hydroxyl radical, since there are no enzymatic defenses against this species of radical [154]. Usually, decreased GSH concentration in tissues is associated with increased lipid peroxidation [155]. Furthermore, in stress conditions GSH prevents the

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loss of protein thiols and vitamin E [156] and plays an important role as a key modulator of cell signaling [157]. Animals and human are able to synthesize GSH. However, even the second level of antioxidant defense in the cell is not able to prevent damaging effects of ROS and RNS on lipids, proteins and DNA. In this case, the third level of defense is based on systems that eliminate damaged molecules or repair them. This level of antioxidant defense includes lipolytic (lipases), proteolytic (peptidases or proteases) and other enzymes (DNA repair enzymes, ligases, nucleases, polymerases, proteinases, phospholipases and various transferases). However, the enzymes of the third level of antioxidant defense do not achieve complete repair or removal of damaged DNA molecules and this could lead to arrest of cell cycle and cell death. In fact, programmed cell death (apoptosis) is involved in maintenance of the genetic integrity by removing genetically altered cells [136]. Cells permanently balance the process of formation and inactivation of ROS. Cells usually tolerate mild oxidative stress by additional synthesis of various antioxidants, in an attempt to restore antioxidant/oxidant balance. However, once the free radical production exceeds the ability of antioxidant system to neutralize them, lipid peroxidation develops and causes damage to unsaturated lipids in cell membranes, amino acids in proteins and nucleotides in DNA and as a result, membrane and cell integrity is disrupted. Membrane damage is associated with a decreased efficiency of absorption of different nutrients and leads to an imbalance of vitamins, amino acids, inorganic elements and other nutrients in the organism. All these events result in decreased productive and reproductive performances of organisms [148]. Environmental pollution, radiation, UV light, cigarette smoke, certain drugs, industrial solvents, chemical reagents and heavy metals (such as Cd) can induce production of free radicals in such an amount that surpasses the ability of the organism to scavenge them leading to detrimental effects. Accordingly, when the amount of Cd in the body exceeds the binding capability of MT, the non-MT-bound Cd ions cause hepato- and nephrotoxicity. One mechanism proposed is that Cd not bound to MT can induce free radicals and lipid peroxidation, which may in turn depress hepatic and renal functions [158-164]. There are several possible sources of ROS following exposure to Cd [165-171]. Phagocytic cells may be an important source of ROS in response to Cd ions [172]. In addition, Cd in spite of not being a Fenton metal per se (unable by itself to generate free radicals directly), can indirectly generate various radicals involving the superoxide radical, hydroxyl radical and nitric oxide, which are capable of influencing the expression of genes [144, 173]. Cadmium disturbs the prooxidant-antioxidant

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balance by damaging the antioxidant barrier as it has been noted to decrease the level of non-enzymatic antioxidants, such as GSH and the pool of sulfhydryl groups, and to inactivate antioxidant enzymes such as SOD, CAT, glutathione reductase and GSH-Px [161, 163]. In detail, Cd exposure indirectly generates ROS formation through depletion of GSH in brain cells and murine thymocytes. The marked decrease in GSH and rise of ROS may also explain the increase in lipid peroxidation after Cd treatment [174]. Treatment with low Cd concentrations leads to depletion of GSH in cultured C6 glioma, murine macrophage, human A549 lung and rat neuronal cells [175]. The same author also found increased lipid peroxidation and inhibition of key antioxidant enzymes in response to Cd exposure and decreased SOD levels in workers exposed to Cd. The antioxidant N-acetylcysteine (NAC) is an important inducer of intracellular GSH and has been shown to be a ROS scavenger in Cd treated rat renal and liver tissue and human lung cells. In apoptotic studies, treatment with antioxidants such as NAC attenuates Cdinduced apoptosis [175]. DNA in each cell of a rat is hit by about 100,000 free radicals a day [176179]. DNA damage may occur via oxidation, methylation, deamination and depurination. The chemistry of attack by ROS on DNA is very complex and lesions in chromatin include damage to bases, sugar lesions, single strandbreaks, basic lesions and DNA-nucleoprotein cross-links [179]. The decrease in the activity or inactivation of antioxidants caused by Cd, together with the generation of radicals may explain the increase in lipid peroxidation and DNA damage [92]. However, it should be mentioned that carcinogenesis is a complex multi-sequence process leading a cell from a healthy to a precancerous state and finally to an early stage of cancer. Several mechanisms have been reported to explain cancer formation. In detail, an increased DNA synthesis and mitosis by nongenotoxic carcinogens may induce mutations in dividing cells through misrepair. Another mechanism that explains the carcinogenic process reports an imbalance between cell proliferation and cell death shifted towards cell proliferation. In addition to these mechanisms, gap junctional intercellular communication (GJIC) (or gap junctions) has been proposed to play an important role in the regulation of cell growth control, differentiation and apoptosis of progenitor cells [144]. There is accumulating evidence that metal ions interfere with distinct steps of diverse DNA repair systems. First indications that metal ions may diminish DNA repair processes were obtained by pronounced comutagenic effects of As3+, Co2+, Ni2+ and Cd2+ in bacteria as well as in mammalian cells [180]. Both Cd2+ and Ni2+ inhibited the repair of the induced DNA damage at low,

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non-cytotoxic concentrations. While Ni2+ diminished the removal of oxidative DNA base modifications as well as the closure of DNA strand breaks, Cd2+ inhibited the repair of the base damage with no impact on DNA strand break processing. Compounds of Ni2+, Co2+, Cd2+ and As3+ have been shown to inhibit the removal of UV-induced DNA damage by interacting with distinct steps of the nucleotide excision repair process [180]. One mechanism of repair inhibition appears to be the displacement of essential metal ions such as Zn2+ in case of Cd2+ and Mg2+ in case of Ni2+ and Co2+. Metal ions are cofactors in many cellular processes and all repair inhibitions were observed at low, noncytotoxic concentrations of the respective metal compounds. Some toxic metal ions exert high affinities towards Zn finger proteins, a family of proteins where Zn is complexed through four invariant cysteine and/or histidine residues forming a Zn finger domain. Zn finger proteins are mostly involved in DNA binding, but also in protein-protein interactions [180]. Zn finger structures are present in transcription factors and have been identified in several DNA repair enzymes. Examples of interactions between carcinogenic metal compounds and Zn finger DNA repair proteins include the inhibition of bacterial formamidopyrimidine-DNA glycosylase protein by Cd2+, Cu2+ and Hg2+ and the inhibition of DNA binding of xeroderma pigmentosum group A protein by Cd2+ and Cu2+ both Ni2+ and Co2+ [180, 181]. It was demonstrated that Cd exposure leads to oxidative damage through the depletion of GSH, increased intracellular ROS formation that cause enhanced lipid peroxidation and protein damage. Nitric oxide, hydroxyl radical, alkoxyl and peroxyl radicals, hydrogen peroxide, aldehydes or other products of lipid peroxidation can all attack protein molecules. The complex structure of proteins and a variety of oxidizable functional groups of the amino acids make them susceptible to oxidative damage. In fact, the accumulation of oxidized proteins has been implicated in the aging process and in other agerelated pathologies [182, 183]. Oxidation of proteins leads to the formation of reversible disulfide bridges. More severe protein oxidation causes a formation of chemically modified derivatives [184]. Oxidation occurs by two different mechanisms: a site-specific formation of ROS via redox-active transition metals and non-metal-dependent ROS-induced oxidation of amino acids [184]. The degree of protein damage depends on many different factors such as the nature and relative location of the oxidant or free radical source; the nature and structure of protein; the proximity of ROS to protein target and the nature and concentrations of available antioxidants [185]. Lipid peroxidation may be mediated by disturbances of natural antioxidant and/or MT levels, which can result in ROS attacking and cleaving the double

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bonds in membrane lipids in the cell. Lipid peroxidation is a chain reaction and potentially large number of cycles of peroxidation could cause substantial damage to cells. It is generally accepted that polyunsaturated fatty acids (PUFA) susceptibility to peroxidation is proportional to amount double bounds in the molecules. In fact, docosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (AA, 20:4n-6) are among major substrates of the peroxidation in the membrane. It is necessary to underline that the same PUFA are responsible for maintenance of physiologically important membrane properties including fluidity and permeability. Lipid peroxidation compromises structure and function of biological membranes [136]. Cadmium induces lipid peroxidation and this has been considered the main cause of its deleterious influence on membrane-dependent functions. Cadmium effects include inhibition of metabolism enzymes such as thiokinase, pyruvate kinase, lactate dehydrogenase, hepatic steroyl-CoA desaturase and microsomal Δ9-desaturase that might contribute to alteration of PUFA metabolism [171, 186-188]. It has been found that Cd is a powerful uncoupling agent of oxidative phosphorylation in mitochondria; therefore, Cd may inhibit thiokinase, which leads to increasing free fatty acid levels [189]. In addition, it was found that Cd reduces the activities of pyruvate kinase and lactate dehydrogenase enzymes, so that the increase in fatty acid levels might be interpreted by increasing the lipolysis rate as a compensatory mechanism for the impairment of carbohydrate metabolism in the energy balance [172]. The increase in saturated fatty acids was attributed to inhibition of some desaturase enzymes. Supporting this finding, it has been reported that Cd treatment suppressed activity of hepatic steroyl-CoA desaturase [186] as well as the activity of microsomal Δ9-desaturase. The total mono- and poly-unsaturated fatty acids were significantly decreased after Cd treatment compared to the control group [190]. Depletion of antioxidants and production of ROS and lipid peroxidation after Cd exposure may play an important role in the etiology of certain diseases like osteoporosis. Osteoporotic women have reduced levels of antioxidants and increased lipid peroxidation [191, 192]. Several studies have found that Se protects animals against toxicity associated with high exposure and/or intake of heavy metals like Cd, Hg, Pb and Ag [193-196]. The presence of Se reduced the availability of metal ions of Cd through the formation of complexes or salts, either soluble or poorly soluble in water [197, 198]. The addition of Se compounds is an efficient therapy against metal toxicity in mammals [199], vegetables [200] and fishes [201]. Treatment of rats with sodium selenite prior to Cd administration prevented or decreased the harmful effects of Cd, because it bound Cd to low

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molecular weight, stable, and biologically inactive Cd selenide complex [202]. Another role of Se is the protection against free radical detrimental effects via the action of selenoproteins. Gan et al., [203] reported that Se supplementation increased the activities of Se-dependent antioxidant enzymes such as GSH-Px and TrxR decreasing free radical-mediated lipid peroxidation and regenerating GSH. Increasing GSH-Px and TrxR activities could be due to the higher Se concentration above the nutritional requirement, which might be sufficient, both to maintain optimal activities for these enzymes and for the detoxification of Cd [172, 204]. Berggren et al., [205] have reported that increased GSH-Px and TrxR activities caused by Se treatment could be due to increased incorporation of selenocysteine, which is essential for their activities. Selenium in an organic form can directly or indirectly effect DNA integrity and repair. For example, elderly male dogs were fed on the diet supplemented with Se in the form of SeMet at 3 μg/kg or 6 μg/kg body weight per day for 7 months and a comparison was made with unsupplemented control dogs. The extent of DNA damage in prostate cells and in peripheral blood lymphocytes, as determined by the alkaline comet assay, was lower among the Sesupplemented dogs than among the control dogs [206]. Furthermore, Seo et al., [207] showed that Se in the form of SeMet induces a DNA repair response in normal human fibroblasts in vitro, and protects cells from DNA damage. A possible mechanism for the DNA repair response was shown to be the enhanced repair complex formation in selenomethionine-treated cells. Kibriya et al., [208] found in a study that many genes, after Se supplementation, were upregulated. Wangher et al., [198] also reported that Se even counteracts the neurotoxicity of Hg, Cd, Pb and V by a mechanism that causes their accumulation in the brain, presumably in a non-toxic complex. Protective effect of Se against DNA damage depends on the dose used. For example, measurements in exocrine cells of the pancreas in hamsters suggested a more rapid repair of single-strand breaks DNA in those hamsters fed 2.5 ppm Se than in those fed 0.1 ppm Se [209]. It has also been shown that Se in the form of SeMet can activate the p53 tumor suppressor protein by a redox mechanism that requires the redox factor Ref1 [210]. SeMet may prevent radiationinduced adverse biological effects by enhancing the DNA repair machinery in irradiated cells. Therefore, it is clear that SeMet has a unique specific effect on the DNA repair system as well as provides a protection against DNA damage and this effect is not the case or even can be opposite when selenite is used [211,212]. Selenium supply improves the protective effect of Zn in the prevention from Cd-induced structural damage in the liver of rats, but not in the kidney

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[213]. In detail, Se-Zn supply practically prevented the histological changes occurring under Cd effect in the liver, whereas in the kidney no additional benefit of the association was noticed compare to Zn supplementation alone. They concluded that simultaneous treatment with Se and Zn may prevent Cdinduced oxidative impair in the kidney and that the restorative effect of Zn and Se co-treatment is better than that of Se or Zn alone [213]. Furthermore, regarding the antioxidant enzymes, it was demonstrated that oral exposure to Cd causes lipid peroxidation and depletion in antioxidant enzyme activities in rat livers, and that Se or Zn may have partial ameliorative effects on these disturbances caused by Cd, whereas Se and Zn together exercise a synergistic effect against the observed oxidative stress [214]. Zinc and Cd are closely located in the periodic table and their molecular homology could be a reason for a compensatory higher Cd resorption. The liver and a number of tissues contain Zn binding proteins, MTs, which sequester Zn and release it by events that signal its requirement [215]. Besides MT’s role in metal homeostasis, the MTs can also serve as store for Zn and Cd, and be involved in metal transfer. The mechanisms by which Cd affects Zn metabolism are not yet well understood but the strong association of Cd and Zn in the liver and kidney most likely is related to the fact that the handling of Cd2+ and Zn2+ in these tissues intersect at several points. Subchronic dietary exposure to Cd has been linked with collateral increases in Zn and Cu concentrations in the liver and kidney [215]. In bovine liver and kidney samples, a significant correlation between Zn and Cu concentrations were observed and may be related to the sharing of transport systems by the metals and the regulatory effects of MTs which can be independently expressed by any of these two metals [215]. Furthermore, Zn has been demonstrated to play an action on preventing oxidative stress, apoptosis and necrosis induced by Cd possibly via the action of Zn dependent antioxidant enzymes like CuZn-SOD [213, 214]. Jacquillet et al., [216] have reported that the effect of co-treatment with Zn during Cd administration completely prevented the changes in renal function produced by the toxic metal in the rat. Zinc deficiency can have detrimental effects in the body since it is required for the optimum activity of more than 200 enzymes, including those involved in the synthesis and repair of DNA and RNA [148, 217, 218]. Cadmium appears mainly to affect the distribution of Zn in the body while Pb appears to produce relative Zn deficiency [219]. Lead and Cd may exert toxic effects on several organ systems, but those on the kidney are the most insidious. Both metals interact with renal membranes and enzymes and disrupt energy production, Ca metabolism, glucose homeostasis and ion transport

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processes [220]. The decreased weight gain in pups after exposure to both metals is an expected toxic effect and has been related to an endocrine disruptor effect of Pb [221], with a reduction in cellular multiplication due to Cd interference with DNA synthesis or with alterations in the bioavailability of essential metals [222]. Heavy metals, including Cd and Pb, are known to interfere with a broad spectrum of solute transport processes in the renal tubule, and the inhibition of Na+/ K+-ATPase by these toxins [223]. This enzyme is located at the basolateral plasma membrane, where it carries out vectorial Na+ transport and thereby provides the gradient for transepithelial fluxes of various ions, nutrients, metabolites, and xenobiotics via Na+dependent transporters. It was found that combined exposure to Pb and Cd reduced residue concentrations of Pb in blood relative to the Pb-alone condition. Furthermore, the biochemical perturbations occasioned by Pb or Cd contamination were attenuated by the joint exposure to both metals [222]. Dietary Fe has an especially prominent effect on the intestinal absorption of Cd and there is a correlation between Fe status and the intestinal absorption of Cd in humans and other mammals [224]. This relationship is particularly evident in anemic adult females [224]. The bioavailability of Cd from a single dietary load was almost three times greater in women than in men [19]. Iron depletion can lead in an increase in the intestinal absorption of Cd [41, 225]. Iron deficiency creates a significant risk for increased Cd exposure by increasing gastrointestinal absorption from 5% to as much as 20% (Lyn Patrick, 2003). In detail, Park et al., [225] showed that the depletion of Fe upregulates DMT1 mRNA in rats, and likely functional DMT1 protein, in the small intestine and increases Cd uptake from the gastrointestinal tract, with subsequent transfer of Cd to the circulation and body tissues. However, Min et al., [226] found that the upregulation of intestinal DMT1 mRNA resulted in a significant increase in tissue Cd accumulation in mice with hemolytic anemia induced by treatment with phenylhydrazine (PHA mice), despite a significant increase in the accumulation of Fe in the liver and kidneys of these mice. These results suggest that the high expression of DMT1 in duodenum coincides with the increased uptake of Cd from the gastrointestinal duct into enterocytes. They concluded that intestinal DMT1 might transport Cd as well as Fe. On the other hand, when excess of Fe (250-270 mg Fe/g) was supplied in the diet of bank voles no histopathological changes in the liver and kidneys due to dietary Cd exposure (40 and 80 mg/g) where noted [227]. Similarly, a protective effect of dietary Fe on decreasing Cd uptake from the gastrointestinal tract was observed in rats [228] and pigs [229]. In contrast, histopathological changes in both organs were observed in the voles exposed

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to dietary Cd even in a quantity of 40 mg/g when fed the Fe adequate diet containing 60-80 mg Fe/g. These data indicate the protective effect of supplemental dietary Fe against Cd-induced tissue injury in these animals [227]. Additionally, human and animal studies have demonstrated that dietary Cd can decrease intestinal Fe absorption and its concentration in the liver and kidneys [227, 230]. It is possible that Cd antagonizes intestinal absorption of the Pb since it was found that rats exposed to Pb and Cd had reduced blood concentrations of Pb compared to exposure to Pb alone [222]. Preceding studies showed that the liver and kidney damage in the bank vole exposed to dietary Cd was accompanied by a dramatic decrease especially in hepatic Fe concentration and lipid peroxidation [231]. Based on these results it was assumed that a deep hepatic Fe depletion, due to dietary Cd, could lead to some disturbances in mitochondrial respiration as evidenced by a decrease in lipid peroxidation, which might also adversely affect ATP production, and an ATP deprivation could eventually cause the hepatocyte disintegration. As a result, hepatic Cd-MT complex (a potent nephrotoxicant) could be released into the circulation and filtered through glomeruli, and then could produce injury to the proximal tubular cells [232]. The Cd content of human bone in North America has increased by a factor of 50 in the last 600 years. The majority of that increase is believed to have occurred in the last 100 years. Classic Cd poisoning (known at itai-itai disease in Japan) has been characterized by multiple fractures, osteomalacia, bone pain and osteoporosis that occur along with renal disease. Normally, absorption of Cd from food is low but absorption is increased if the animals are on a low Ca diet. The most sensitive cellular targets of Cd seem to be ion transport and signal transduction. These include intracellular mobilization of second messengers such as InsP3 and Ca, inhibition of plasma membrane Ca channels and inhibition of Ca2+-ATPases of the sarcoplasmic reticulum [172]. Epidemiological studies have found a positive correlation between elevated urinary Cd levels and increased urinary Ca loss and elevated serum alkaline phosphatase levels. The mechanisms behind Cd and bone loss are related to renal tubular cell damage, that results in elevated levels of urinary Ca and lowered levels of 1,25 dihydroxy-cholecalciferol, a consistent finding in women environmentally exposed to significant levels of Cd. Lower levels of activated vitamin D3 alter Ca homeostasis by decreasing absorption of Ca in the gut and altering deposition in bone [23]. Cadmium induced carcinogenesis may be due to activation of mitogenic signaling pathways because Cd ions interact with cellular Ca homeostasis causing a sustained activation of mitogen-activated protein kinases that are correlated with the induction of c-

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fos [37]. This hypothesis together with the inhibition of DNA repair and the antagonism of cytoprotective mechanisms by Cd, may explain the complex multi-sequence process of carcinogenesis [2]. Diet-derived antioxidants such as β-carotene, ascorbate and tocopherols are important in maintaining human health. There is accumulating evidence that Cd toxicity is associated with a marked decrease in several dietary antioxidants. Vitamin E protects critical cellular structures against damage caused by oxygen-free radicals and reactive products of lipid peroxidation. ElDemerdash, et al., [233] reported that vitamin E and β-carotene alone or in combination produced a significant reduction in CdCl2-induced increase in thiobarbituric acid reactive substances (TBARS) in different rat tissues. The same authors reported that because of ameliorated oxidative stress and ROS, the activities of plasma, liver, testes and brain enzymes were partially restored. They concluded that adequate antioxidant status may attenuate Cd-induced oxidative stress and cellular damage. Additionally, flavonoids are one of the most numerous and widespread group of naturally occurring antioxidants that can inhibit lipid oxidation in a biological membrane. They are found in fruits, vegetables, nuts, seeds, leaves, flowers and barks of plants. They usually contain one are more aromatic hydroxyl groups in their moiety, which is responsible for the antioxidant activity of the flavonoids. Recently, the flavonoid Naringenin (4’,5,7-trihydroxy flavonone), a plant bioflavonoid found in citrus fruits, has been evaluated as a potential antioxidant [234]. The same authors demonstrated that naringenin can protect against Cd-induced oxidative damage in the kidney of rats. Naringenin effectiveness is due to quenching of free radicals, antioxidant and metal chelating ability. The chelating property of naringenin enhances the elimination of Cd from the renal tissue, which may reduce the Cd burden with displacement of metal cofactors and/or Cd binding with enzymes. In addition, the capability of naringenin to react with free radicals or with highly reactive by products of lipid peroxidation as well as enhancement of tissue thiol pools may be responsible for the reduction of oxidative modification for enzymes and a reversal of the activities of antioxidants and GSH metabolizing enzymes [234].

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Chapter 6

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CONCLUSION Cadmium is a heavy metal found as an environmental contaminant, both through natural occurrence and from industrial and agricultural sources. Foodstuffs are the main source of cadmium exposure for the non-smoking general population. Cadmium absorption after dietary exposure in humans is relatively low but cadmium is efficiently retained in the kidney and liver in the human body, with a very long biological half-life. Due to its long half-time is a cumulative toxin and may cause renal failure, bone demineralization and neoplasmatic transformations; that is why, IARC has classified cadmium as a human carcinogen [43]. Cadmium bioavailability, retention and consequently toxicity are affected by several factors such as prolonged occupational exposure, smoking, preexisting diseases and nutritional status. Only in the case of balanced diet and sufficient provision of dietary antioxidant nutrients, the defense is effective [235]. All antioxidants in the body are working in synergy to provide antioxidant defense. The co-operative interactions between antioxidants in the cell are vital for maximum protection from the deleterious effects of free radicals and toxic products of their metabolism. On the other hand, under high stress conditions, free radical production is increased dramatically. Free radical overproduction and oxidative stress are considered as a pathobiochemical mechanism involved in the initiation or progression phase of various diseases. During these times of excessive radical production without supplementation with increased concentrations of natural antioxidants is difficult to prevent damage to major organs and systems [136]. In general, ingestion of excessive amounts of antioxidants is presumed to shift the oxidant-antioxidant balance toward the antioxidant side. This is supposed to be beneficial; however, this may also adversely affect key physiological

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processes that are dependent on free radicals, including prostaglandin production, cell division and differentiation [236]. Marginal deficiencies of the essential nutrients like Zn, Fe and Ca affect the enhancement of absorption and accumulation and retention of dietary Cd in the organism. These marginal deficiencies enhanced Cd absorption as much as ten-fold from diets containing low Cd concentrations indicating that people who are nutritionally marginal with respect to Zn, Fe and Ca are at higher risk of Cd disease than those who are nutritionally adequate [237]. There is a variety of natural and anthropogenic sources of heavy metals like Cd, Pb, Zn, Cr, Cu and Ni in the environment [238]. Cadmium is present in nature and will always be present in our society, either in useful products or in controlled wastes. Today, its health effects are understood and if Cd environmental emissions are well regulated there will be no need to restrict or ban Cd products. Furthermore, recycling programs can conserve valuable natural Cd resources. Recycling will contribute to the sustainable and safe use of Cd in our society.

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Surai, P. F.. Cadmium Toxicity and the Antioxidant System, edited by A.C. Pappas, et al., Nova Science Publishers,

INDEX A

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Absorption, 10, 19, 29, 35, 36, 39, 40 Accumulation, 13, 16, 19, 31, 33, 35, 40 Administration, 5, 17, 21, 33, 34 Albumin, 14, 19, 21, 27 Animal, 1, 10, 14, 15, 29, 32, 36 Antioxidant, 23, 26, 28, 29, 30, 32, 33, 34, 37, 39

B Battery, 3, 4, 10 Binding, 9, 15, 16, 19, 21, 27, 29, 31, 34, 37 Blood, 4, 17, 21, 25, 33, 35, 36 Bone, 11, 15, 36, 39 Brain, 20, 24, 30, 33, 37

C Cadmium, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 13, 14, 15, 16, 17, 19, 20, 21, 23, 29, 30, 31, 32, 34, 35, 36, 37, 39 Calcium, 15, 19, 20, 21, 23, 35, 36, 40 Cancer, 1, 10, 13, 15, 23, 25, 30 Carcinogen, 1, 10, 13, 30, 39 Carcinogenesis, 15, 30, 37 Catalase, 26, 30

Cell, 14, 15, 16, 19, 20, 21, 23, 26, 27, 28, 29, 30, 31, 32, 33, 36, 39 Complex, 19, 20, 21, 30, 31, 32, 36, 37 Copper, 1, 4, 5, 9, 25, 34, 40

D Damage, 14, 15, 16, 21, 23, 27, 28, 29, 30, 31, 32, 33, 34, 36, 37, 39 Defense, 27, 29, 39 Deficiency, 40 Diet, 10, 17, 33, 35, 36, 37, 39 Disease, 10, 14, 15, 23, 24, 32, 36, 39 DNA, 15, 16, 27, 28, 29, 30, 33, 34, 37 Dust, 3, 4, 7, 13, 14

E Effect, 4, 10, 13, 14, 15, 16, 17, 21, 24, 25, 28, 29, 31, 32, 33, 34, 35, 39 Environment, 1, 2, 4, 23, 40 Essential, 19, 31, 33, 35, 40 Excretion, 14, 21 Exposure, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 17, 19, 21, 29, 31, 32, 34, 35, 39

Surai, P. F.. Cadmium Toxicity and the Antioxidant System, edited by A.C. Pappas, et al., Nova Science Publishers,

Index

64

F Fertilizer, 1, 2, 9 Food, 3, 9, 10, 11, 13, 36 Free radical, 23, 24, 25, 26, 27, 28, 29, 30, 31, 33, 37, 39 Fume, 3, 5, 7, 13, 14

G Gene, 15, 16, 23, 30, 33 Glutathione, 16, 21, 26, 28, 30, 31, 33, 37 Glutathione peroxidase, 26, 30, 33

H

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Heart, 20, 24 Heavy metals, 1, 24, 29, 32, 35, 40 Homeostasis, 19, 26, 34, 35, 36 Human, 1, 2, 10, 13, 15, 16, 19, 20, 21, 24, 29, 30, 33, 35, 36, 37, 39

I Industry, 1, 3, 4, 5, 6 Ingestion, 3, 4, 13, 19, 20, 39 Intake, 10, 13, 15, 32 Intestine, 20, 21, 35 Ion, 2, 16, 17, 19, 21, 29, 30, 32, 35, 36 Iron, 6, 19, 21, 24, 25, 35, 40

K Kidney, 10, 11, 13, 14, 16, 20, 21, 24, 34, 35, 37, 39

L Lead, 1, 4, 5, 16, 25, 29, 32, 34, 35, 40 Liver, 10, 20, 21, 24, 30, 34, 35, 37, 39 Lung, 10, 13, 14, 15, 16, 20, 21, 24, 30

M Mechanism, 15, 16, 17, 19, 20, 23, 27, 29, 30, 31, 32, 33, 34, 36, 39 Membrane, 20, 29, 32, 35 Metabolism, 15, 19, 28, 32, 34, 35, 39 Metal, 1, 2, 3, 5, 7, 8, 9, 16, 17, 19, 20, 27, 29, 30, 31, 32, 34, 35, 37, 39 Metallothionein, 16, 19, 20, 21, 27, 29, 32, 34, 36 Mortality, 15 Mutation, 15, 30

N Nickel, 1, 3, 4, 15, 40 Nutrient, 29, 35, 39

O Oral, 15, 19, 21, 34 Oxidation, 9, 25, 30, 31, 37 Oxide, 1, 5, 9, 14, 25, 26, 30, 31

P Peroxidation, 27, 29, 30, 31, 32, 33, 34, 36, 37 pH, 9 Phosphate, 9, 15 Pigment, 3, 4, 6, 8, 10 Production, 1, 3, 4, 5, 6, 9, 15, 21, 23, 26, 29, 32, 35, 36, 39 Protection, 3, 10, 17, 19, 21, 27, 33, 39 Protein, 9, 14, 16, 19, 20, 21, 23, 26, 27, 28, 29, 31, 33, 34, 35, 37 Proteinuria, 14

R Retention, 19, 20, 39 Risk, 2, 10, 35, 40 ROS, 16, 23, 26, 28, 29, 30, 31, 32, 37

Surai, P. F.. Cadmium Toxicity and the Antioxidant System, edited by A.C. Pappas, et al., Nova Science Publishers,

Index

S Selenium, 24, 27, 32, 34 Selenoprotein, 27, 33 Smoke, 10, 25, 29 Smoking, 3, 10, 25, 29, 39 Soil, 1, 9, 13 Source, 3, 9, 10, 21, 23, 25, 26, 29, 31, 39, 40 Stress, 16, 26, 29, 34, 37, 39 Study, 1, 14, 15, 16, 17, 21, 30, 32, 36 Sulphide, 14 Superoxide dismutase, 26, 30, 34 System, 4, 9, 13, 14, 15, 20, 21, 23, 24, 26, 29, 33

T

Toxic, 1, 3, 10, 14, 16, 24, 25, 31, 33, 34, 35, 39 Transporter, 16, 20, 35 Tumor, 17, 33

U Uptake, 9, 19, 35 Urinary, 14, 21, 36

V Vitamin, 15, 26, 29, 36, 37

W Worker, 1, 4, 5, 6, 7, 8, 10, 13, 14, 15, 16, 30

Z Zinc, 1, 3, 4, 5, 9, 16, 17, 19, 20, 31, 34, 40

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Thioredoxin, 26, 27 Thioredoxin peroxidase, 27 Thioredoxin reductase, 27, 33 Tissue, 15, 19, 20, 29, 30, 34, 35, 37

65

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